Polyurethane-biopolymer composite

ABSTRACT

A method is provided for preparing a drug delivery material and device comprising cross-linking a biological polymer with a cross-linking agent and loading the cross-linked biopolymer with a bioactive agent. Preferred embodiments are disclosed wherein the drug delivery material is used in a catheter securing, drug delivery device, in a wound dressing, and in a wound dressing for percutaneous catheters.

This application is a continuation of application Ser. No. 08/947,189now U.S. Pat. No. 6,071,447 filed Oct. 8, 1997, which is a continuationof application Ser. No. 08/751,419, filed Nov. 18, 1996, now abandoned,which is a continuation of application Ser. No. 08/058,510, filed May 4,1993, now abandoned which is a continuation-in-part of application Ser.No. 07/539,990, filed Jun. 14, 1990, now abandoned.

The present invention is related to a polymeric delivery vehicle fordelivery of bioactive agents, and in particular, for the delivery ofantimicrobial agents. The invention is also directed to acatheter-securing and drug delivery device comprising, as a componentthereof, a material which delivers antimicrobial and/or otherwound-healing factors at the site of the insertion of the catheter intothe body.

BACKGROUND OF THE INVENTION

Techniques have been developed for administering pharmaceuticals throughthe skin by absorption. Such techniques are accomplished by deviceswhich typically comprise either a pharmaceutical-containing reservoirenclosed by a synthetic membrane through which the pharmaceutical candiffuse at a controlled rate, or a dispersion of a pharmaceutical in asynthetic polymer matrix in which the pharmaceutical can diffuse at acontrolled rate. While such delivery devices work for somepharmaceuticals, the rate of release of other pharmaceuticals is notadequate through synthetic polymers. Either the rate of delivery is tooslow to provide an effective dosage given the area of the deliverysurface, or in some cases, where prolonged delivery of the drug isdesired, delivery is too fast so that the device must be replaced withina short period of time. One situation in which it is desirable to have adrug delivered over a prolonged period of time without removal of thedelivery device is the case of delivery of drugs at a wound site arounda percutaneous medical device.

Moreover, it is desirable, particularly when dealing with delivery ofbioactive agents which are natural products, such as growth factors,that the polymeric matrix from which the drug is delivered be tailoredfor optimal drug delivery rate. It is difficult to do this when the drugto be delivered is a biological macromolecule, such as an enzyme orsurface receptor, since specialized binding functionalities with propercharge density, orientation, hydrophobic domains, etc. are not readilysynthesized into synthetic polymers to release the biologicalmacromolecule at a desired controlled rate.

It is thus an object of the present invention to provide a polymericdelivery compositions for controlled release of bioactive agents,particularly biological macromolecules, which is formed of a foamcomposite of a biopolymer and a synthetic polymer.

It is another object of the present invention to provide drug deliverydevices, particularly wound dressings, containing such polymericdelivery vehicles for controlled release of antimicrobial and/orwound-healing agents to aid in the wound healing process.

It is another object of the present invention to provide acatheter-securing and drug delivery device which is easily used whichcontains a pad comprising a biopolymer which serves as a deliveryvehicle for controlled release of a bioactive agent to the catheterwound site.

These and other objects of the invention will be apparent from thefollowing description and appended claims, and from practice of theinvention.

SUMMARY OF THE INVENTION

The present invention provides a method for preparing a polymericdelivery vehicle for controlled release of a bioactive agent. The methodcomprises the steps of cross-linking a biopolymer which containschemically reactive functionalities which react with a cross-linkingreagent, where the cross-linking agent comprises greater that tworeactive sites per molecule which are chemically reactive withfunctionalities on the biopolymer, to form a cross-linked biopolymer;optionally, forming the cross-linked biopolymer into a desired shape;then contacting the cross-linked biopolymer with a bioactive agent toreversibly bind the bioactive agent to the biopolymer to form thepolymeric delivery vehicle. Preferably, the cross-linking reagent is apolyurethane or polyurethane urea having isocyanate side groups and/orend groups. It will be appreciated that the number of reactive sites permolecule of the cross-linking agent is a statistical average, thereforesome cross-linking molecules will contain two or less reactive sites.Alternatively, the bioactive agent is bound to the biopolymer beforetreatment with the cross-linking agent. By effective binding affinity itis meant that the bioactive agent can be bound (noncovalently) to sitesin the biopolymer; then, when in use in contact with skin and/or bodilyfluids, or other fluids, a substantial amount of the bioactive agentwill be released from the biopolymer, with release sustained for aperiod of time, controlled by the binding affinity.

As used herein, the term “binding affinity” is the ratio of the amountof bound drug (the bioactive agent) to the amount of free drug, wherein

[Bound drug]=[the total amount of drug found in a biopolymer samplewhich is contacted with a solution of drug and allowed to equilibrate]minus [the volume of solution absorbed by the biopolymer times theconcentration of drug in the remaining unabsorbed solution]

[Free drug]=[the total amount of drug found in the biopolymer sample]minus [Bound drug].

Thus,${{Binding}\quad {affinity}} = {\frac{\left\lbrack {{Bound}\quad {drug}} \right\rbrack}{\left\lbrack {{Free}\quad {drug}} \right\rbrack} = \frac{\left\lbrack {{Bound}\quad {drug}} \right\rbrack}{\left\lbrack {{Total}\quad {drug}} \right\rbrack + \left\lbrack {{Bound}\quad {drug}} \right\rbrack}}$

Generally, a higher binding affinity provides a longer sustained releaseof drug. Particularly preferred compositions have binding affinitiesover 0.8, preferably 1.0 and higher. Useful compositions have a bindingaffinity for the drug in the range of 1.0 to 5.0.

In a preferred embodiment of the present invention, the polymericdelivery vehicle is used in a catheter-securing and drug deliverydevice. The device comprises an elastomeric pad having a radial slitextending from the edge of the pad to a central point proximate to thecenter of the pad. The pad comprises a cross-linked biopolymer and abioactive reagent reversibly bound thereto, wherein the bioactivereagent is releasable from the cross-linked biopolymer in a controlledmanner to a wound or to the skin. The device further comprises areinforced, flexible, water vapor permeable membrane adhesively attachedto the pad which extends beyond the edge of the pad on all sidesthereof, thereby forming a flange surrounding the pad. At least theedges of the exposed bottom surface of the membrane is coated with anadhesive material for affixing the device to the skin. The membrane hasanother radial slit extending from the edge of the membrane, through themembrane toward the central point of the pad, which is colinearallyaligned with the slit in the pad. Finally, the device optionallycomprises a reinforced, flexible, water vapor permeable tab affixed tothe upper surface of the membrane and located proximate to one side ofthe pad wherein one surface of the tab is adhesively coated and the tabhas dimensions sufficient to cover the pad when the tab is folded foradhesive attachment to the upper surface of the pad.

In another preferred embodiment the polymeric delivery vehicle in theform of an elastomeric pad is used as a wound dressing. The pad may besecured upon a wound by an adhesive water-vapor film over the pad whichadheres to the skin area surrounding the wound.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the weight of chlorhexidene gluconate releasedversus time from two types of polyurethane-modified biopolymers and froma polyurethane control polymer.

FIG. 2 is a graph of drug loading (silver ion) as a function of amountof biopolymer (gelatin) in a gelatin-polyurethane composite sponge.

FIG. 3 is a graph of a typical drug (silver ion) release rate from acomposite of polyurethane —22% gelatin.

FIG. 4 is a perspective view of a preferred embodiment of acatheter-securing and drug delivery device according to the presentinvention.

FIG. 5 is a side view of the device shown in FIG. 4.

FIG. 6 is a perspective view of a catheter-securing device accommodatinga catheter.

FIG. 7 is a plan view of a wound dressing according to the presentinvention.

FIG. 8 is a graph of silver ion concentration versus gelatinconcentration found according to the test in Example 3.

FIG. 9 is a graph of silver ion content in cross-linkedpolyurethane/gelatin sponges v. gelatin content found according to thetest in Example 4.

FIG. 10 is a graph of drug affinity in cross-linked polyurethane/gelatinsponges v. gelatin content found according to the test in Example 4.

DETAILED DESCRIPTION OF THE INVENTION

The polymeric delivery vehicle for controlled release of a bioactiveagent according to the present invention may be formed by treating abiopolymer with a cross-linking agent whereby the cross-linking agent issimultaneously polymerized and formed into cross-linking moieties withthe biopolymers. The preferred cross-linking agents arepolyisocyanate-terminated polyurethane or polyurethane urea pre-polymerswhich are known in the art. If water is used as a solvent the reactionof the polyurethane or polyurethane urea cross-linking agent via theisocyanate side and/or end groups of the cross-linking agent is carbondioxide which results in a foam material. If non-protic solvents areused, a solid (unfoamed) polymeric composite will result. A material maybe cast into films, slabs or molded into desired shapes.

The biopolymers which are to be treated with a cross-linking agentaccording to the present invention include, but are not limited toproteins, peptides and polysaccharides, such as:

Biopolymer Biological Source 1. Polygalacturonic acid Citrus peels 2.Hydroxypropyl celluose Wood 3. Hydroxyethyl celluose Wood 4. HeparinPorcine intestine 5. Collagen Animal tendon, hide 6. Gelatin Animal hide7. Carboxymethyl celluose Wood 8. Pectin Citrus peels 9. Algin Kelp 10.Ethyl celluose Wood 11. Glycosaminoglycan Animal Tissues 12.Chitin/Chitosan Arthropods 13. Other polysaccharides —

Preferred biopolymers are gelatin, collagen, and polysaccharides,particularly cellulose derivatives, as, for example,hydroxyethylcellulose.

The biopolymers which have a binding affinity above 0.8 with bioactiveagents will typically have charged or highly polar groups in order tobind to bioactive agents containing highly polar or charged groups ofthe opposite charge from those on the biopolymer. Thus, the binding willoccur by ionic interaction between the charged groups. Typicalbiopolymers containing charged groups are collagen, gelatin,hydroxyethylcellulose, and other polymers containing groups which can becharged, such as, —N⁺H₃ and −CO₂, or which are highly polar, such as,—OH and —SH.

The thickness of the polymeric matrix may be varied as desired,depending upon the desired pharmaceutical dosage and duration ofdelivery. Ordinarily, a suitable matrix thickness will be in a range ofabout 0.1 to 1.0 centimeters.

The ratio of cross-linking agent to biopolymer will depend in part onthe particular biopolymer and the bioactive agent with which it isintended to be used. It will be understood that mixtures of differentbiopolymers may also be utilized. However, generally, it will be usefulto employ a weight ratio of cross-linking agent to biopolymer of fromabout 20:1 to about 1:1. It will be realized that suitablepolymerization initiators may be utilized to initiate the polymerizationreaction, which include, but are not limited to azobisisobutylnitrile,peroxide initiators, such as benzoyl peroxide, isopropyl peroxide, andthe like. Although polyurethane and polyurethane ureas are the preferredcross-linking agents, other cross-linking agents may be suitable, suchas alkylene polyacrylates, alkylene polymethacrylates, alkyleneglycolpolymethacrylates, polyalkylene glycolpolymethacrylates,polyaldehydes as well as other cross-linking agents which willcross-link molecules with reactive protic groups. The cross-linkingagents will have greater than two reactive sites/molecule, so the agentsare statistically determined to be at least triacrylates, trialdehydes,and the like. The molecular weights of the cross-linking agents are alsogreater than about 500 (weight average), preferably greater than 1000. Apreferred cross-linking agent is a polyether polyisocyanate sold asHypol® Foamable Hydrophilic Prepolymer by W. R. Grace & Co. (Lexington,Mass.), which has greater than 2 free isocyanate groups/molecule. Unliketypical difunctional agents, cross-linking agents having greater than 2reactive groups per molecule (a statistical average) can greatly affectcrosslink density and enhance mechanical properties of the crosslinkedmaterial. The molecular weights are typically 1300-1400 (weightaverage).

It will be realized from the teachings herein that the degree ofcross-linking, thickness and/or shape of the cross-linked biopolymer,and the degree of porosity (if any) are all parameters which may becontrolled to attain a desired release profile of the bioactive agentfrom the cross-linked biopolymer. Furthermore, the biopolymer may bechemically modified to change its binding affinity for a selectedbioactive agent. For example, hydroxyethyl cellulose may be partiallymethylated to reduce the number of cross-linking sites and/or potentialchelating sites, depending upon whether the cross-linking is performedbefore or after the bioactive agent is impregnated into the biopolymer.

The shape of the cross-linked biopolymer may be formed by molding orcasting before cross-linking or, after cross-linking, it may be formedinto a desired shape by cutting. The cross-linked biopolymer will thenbe loaded with the desired bioactive agent(s), which is believed tooccur by ionic binding involving ionic sites on the biopolymer, with thedesired bioactive agent, which may be antimicrobial drugs ormacromolecules such as growth factors, antibacterial agents,antispasmodic agents, or any other active biological bioactive agent,such as adrenergic agents such as ephedrine, desoxyephedrine,phenylephrine, epinephrine and the like, cholinergic agents such asphysostigmine, neostigmine and the like, antispasmodic agents such asatropine, methantheline, papaverine and the like, tranquilizers andmuscle relaxants such as fluphenazine, chlorpromazine, triflupromazine,mephenesin, meprobamate and the like, antidepressants likeamitriptyline, nortriptyline, and the like, antihistamines such asdiphenhydramine, dimenhydrinate, tripelennamine, perphenazine,chlorprophenazine, chlorprophenpyradimine and the like, hyptotensiveagents such as rauwolfia, reserpine and the like, cardioactive agentssuch as bendroflumethiazide, flumethiazide, chlorothiazide, aminotrate,propranolol, nadolol, procainamide and the like, angiotensin convertingenzyme inhibitors such as captopril and enalapril, bronchodialators suchas theophylline, steroids such as testosterone, prednisolone, and thelike, antibacterial agents, e.g., sulfonamides such as sulfadiazine,sulfamerazine, sulfamethazine, sulfisoxazole and the like, antimalarialssuch as chloroquine and the like, antibiotics such as the tetracyclines,nystatin, streptomycin, cephradine and other cephalosporins, penicillin,semi-synthetic penicillins, griseofulvin and the like, sedatives such aschloral hydrate, phenobarbital and other barbiturates, glutethimide,antitubercular agents such as isoniazid and the like, analgesics such asaspirin, acetaminophen, phenylbutazone, propoxyphene, methadone,meperidine and the like, etc. These substances are frequently employedeither as the free compound or in a salt form, e.g., acid additionsalts, basic salts like alkali metal salts, etc. Other therapeuticagents having the same or different physiological activity can also beemployed in the pharmaceutical preparations within the scope of thepresent invention. Typically, the bioactive agent dissolved in asuitable solvent will be contacted with the cross-linked biologicalpolymer by immersion. The loading of the biopolymer may be readilydetermined based upon the uptake of the biopolymer of the bioactiveagent.

In a preferred method for forming the loaded cross-linked biopolymer,the bioactive agent is dissolved in water at a suitable concentration,typically about 1-2% by weight, and the cross-linked biological polymeris immersed therein for a period of about 240 minutes. At ambienttemperature (about 20-25° C.), the biopolymer is then extracted from thesolvent, allowed to air dry or is lyophilized, and is then ready foruse.

Alternatively, the cross-linked biopolymer may be loaded with thebioactive agent, then dried, then cut to a suitable form for use.

In another preferred method, the bioactive agent and biopolymer aredissolved in an aqueous solvent before cross-linking and the bioactiveagent is bound to the biopolymer. Typical agent: biopolymer weightratios are in the range of about 1:100 to 5:100 in solution. Thebiopolymer is then cross-linked by treatment with the cross-linkingagent.

It will be realized that the biopolymer material may be modified, forexample, so as to be made more hydrophilic or hydrophobic to adjust forsuitable binding properties to the bioactive agent. Such modificationmay be performed by, for example, esterification of acid groups in thebiopolymer prior to cross-linking, thus making the biopolymer morehydrophobic.

The general reactions for a typical treatment of a biopolymer havingprotic groups (—HX) with polyisocyanate are shown below in Table 1.

TABLE 1 General reaction of polyisocyanate with acidic groupO═C═N—R—N═C═O + —XH

FOAMING:

Referring to the figures, in FIG. 1 there is shown a graph of drugrelease of chlorhexidene gluconate from two biopolymers as compared to acontrast polymer. The control polymer is polyurethane (PU). One of thetest foams is polyurethane cross-linked (10 wt. %) collagen andpolyurethane cross-linked (10 wt. %) hydroxyethyl celluose (HEC). Thefoams and control were soaked in a 2% solution of chlorhexidenegluconate (CHXG) for the same period of time. To measure the drug effluxfrom each of the biopolymers, each was placed in a large reservoir ofphysiological saline and the bathing medium was changed daily tomaintain sink conditions. As shown in FIG. 1, the drug was releasedquickly and completely from the control foam by the fifth day. A morecontrolled release was achieved in the cross-linked hydroxyethylcelluose, with the drug still being slowly released after 13 days.Release from HEC can extend beyond 13 days, but in that test theexperiment was stopped after 13 days. A more extended release profile isshown in the cross-linked collagen, with drug release occurring even upto 17 days, when the experiment was stopped. Moreover, it can be seenfrom the graph that a greater amount of CHXG was released from the twotest samples than from the control. Although the HEC test was haltedafter 13 days, its CHXG release curve was still on an upward slope, andit already had released about as much CHXG as the control.

In FIG. 2 there is shown a graph of drug loading, where the drug is asilver ion, as a function of the amount of gelatin (biopolymer) in agelatin-polyurethane composite sponge. It can be seen that without thebiopolymer (0% gelatin) there is essentially no binding taking placewhereas the drug binding increases with increasing amount of biopolymerpresent in the composite.

Referring to FIG. 3 there is shown a graph of a chemical drug releaserate (of silver ion) from a composite of polyurethane —22% gelatin. Itcan be seen that there is a surge of drug release during the first day,then in the second day, continuing to the tenth day (the end of theparticular test) there is a relatively constant rate of release of thedrug from the composite.

Referring to FIG. 4, there is shown a preferred embodiment of thepresent invention in a catheter-securing and drug delivery device. Thedevice comprises a reinforced, flexible, water vapor permeable membrane10, a portion of which is upturned as a flap 11. Membrane 10 may be madeof any water vapor permeable synthetic polymer such as a polyurethane orpolyester reinforced with thread. At least the edges of the bottomsurface of membrane 10 (including flap 11) are coated with an adhesive(not shown). Alternatively, the entire bottom surface of membrane 10(including flap 11) may be coated with an adhesive. On the bottomsurface of the membrane 10, about centrally located thereunder, isaffixed an elastomeric pad 16. The elastomeric pad 16 will be across-linked, biological polymer loaded with a bioactive agent modifiedaccording to the present invention. Preferably, the biopolymer comprisesa cross-linked hydroxyethyl cellulose and the bioactive agent is anantimicrobial agent such as chlorhexidene gluconate. Both the membrane10 and the pad 16 are adapted with slit 18, with the slit in pad 16being collinear with the slit in the membrane 10. Both slits terminateat a point 19 located proximate to the center of the pad 16. At point 19the pad 16 and membrane 10 will surround a catheter (not shown) wherebythe membrane 10 and pad 16 serve as a catheter fixing device. The pad 16additionally serves as a drug delivery component for deliveringantimicrobial agents or other agents to the wound caused by thecatheter. Thus, pad 16 may be used without membrane 10, in analternative embodiment, in which case at least the edges of the bottomsurface of pad 16 will be coated, impregnated, or otherwise adapted withan adhesive material.

Returning to FIG. 4, on the upper surface of the membrane 10 andadjacent to the central point 19 is shown an optional pillow 17 which,may also be made of a cross-linked biological polymer loaded with anantimicrobial agent according to the present invention. The purpose ofthe pillow 17 is for receiving and supporting the side of the catheter(not shown), since catheters may extend from the skin surface at anoblique angle. The extension of the catheter from the skin may be restedupon the pillow 17. Adjacent to the slit 18 is flap 14 which may be madeof the same reinforced, flexible, water vapor permeable material asmembrane 10 and is affixed to membrane 10. The flap 14 is shown in anopen position, therefore the reinforced, flexible, water vapor permeablemembrane is on the underside and not seen in the figure. The flap 14 iscoated with an adhesive (not shown) and the adhesive is protected by aremovable protecting layer (such as, paper or plastic) 15. Once thecatheter is in place at central port 19 the flap 14 is folded over thecatheter and, by removal of layer 15, the flap 14 is adhesively attachedover a portion of the slit 18, the pillow 17, a portion of the catheter(not shown) as well as over a portion of the upper surface of themembrane 10. This serves not only to affix the catheter but also tomaintain the slit 18 in a closed position.

In an alternative embodiment, still referring to FIG. 4, the device maybe used as a wound dressing for use with percutaneous catheters withoutthe catheter-securing feature of flap 14 (and protecting layer 15) byassembling the device without these items. Without flap 14, the pillow17 may also be optionally deleted.

Before use, the bottom adhesively coated surfaces of membrane 10(including flap 11) are protected, as shown, by three removable layers12, 13 a, 13 b (made, for example, of paper or plastic). First, layer 12is removed and the catheter is pulled through slit 18 until it isengaged at central point 19. The adhesive portion of flap 11 is thensecured to the skin. Then layers 13 a and 13 b are removed and theremainder of the membrane 10 is secured to the skin. Finally, thecatheter is securely placed onto pillow 17 (if present) and flap 14 isfolded over, and, after removal of layer 15, flap 14 is secured over thecatheter and membrane 10.

A particular advantage of the device shown in FIG. 4 is that it islight, easily used and disposable, as opposed to other catheter-securingdevices which accommodate complex mechanical parts, some of which mustbe sterilized for re-use. Another advantage of the device shown in FIG.4, particularly when used in conjunction with the cross-linkedbiopolymer according to the present invention, is that it can administerat the wound site of the catheter not only an antimicrobial agent, butalso growth factors or other desirable bioactive agents which wouldassist not only in combating infection, but also in healing of thewound. If desired, an immune-modulating factor may also be incorporatedinto the device for those patients who may have allergic reaction to thebioactive agent.

Referring to FIG. 5 there is shown a side view of the device shown inFIG. 4. As can be seen in FIG. 5, the removable layer 13 a (as well as13B) is actually folded over onto itself so that when it is pulled in adownward direction (as shown in FIG. 5) it can be pulled away withoutchanging the positioning of the device.

Referring to FIG. 6 there is shown the device of FIG. 4 accommodating acatheter 20 which has been inserted into central point 19 by slippingthrough slit 18.

Referring to FIG. 7 there is shown a wound dressing comprising aflexible moisture permeable membrane 30 having an adhesive surfaceprotected by a removable layer 31, a portion 32 of which extends beyondthe membrane 30 for convenience. Approximately centrally located on theunderside of membrane 30 is an elastomeric pad 33 made of a materialaccording to the present invention (preferably, abiopolymer-polyurethane containing an antimicrobial agent) which is tobe placed in direct contact with the wound. This dressing may also beutilized as a drug delivery device, particularly to deliverantimicrobial agents and wound-healing agents. An immune-modulatingfactor may also be used if the patient exhibits an allergic reaction tothe antimicrobial agent.

The following examples are presented for the purpose of illustration andare not intended to limit the invention in any way.

EXAMPLE 1

To a 2.5% (w/v) solution of hydroxyethylcellulose is added (1:1 weightratio) anhydrous polyisocyanate-terminated urethane pre-polymer. Themixed composite is placed in an open vessel, and cured for about 30minutes at R.T. to form a “bun”. The bun is cut into a desired shape andplaced in a 2.5% (v/v) solution of 22% chlorhexidine gluconate (adjustedat pH 8.0 with ammonium hydroxide). After incubation for 4 hours, thesponge is removed, frozen and lyophilized.

EXAMPLE 2

In an aqueous solution of gelatin (120 g/100 ml water), adjusted to pH7.6, is added silver nitrate to the desired silver ion concentration,and the mixture is stirred for at least 4 hours in a brown glass bottle.The pH is adjusted to 7.2 and stirring is continued for 2 hours. The 36parts of anhydrous polyisocyanate-terminated urethane prepolymer isadded per 64 parts of the gelatin-silver solution. The mixture is placedin an open vessel and allowed to cure for 30-45 minutes at R.T. to forma bun. The bun is cut into desired shapes and washed in deionized water.

EXAMPLE 3 Determination of Drug Binding to Biopolymer

Saturated solutions of silver carbonate at pH 7 were prepared withvarying levels of gelatin. The silver in solution was measured for thesamples to determine the binding constant for silver to gelatin underthese conditions. FIG. 8 is a graphical representation of the results,demonstrating that gelatin appreciably binds silver ion, increasing thesolution concentration of silver. Due to its ability to bind silverions, gelatin is a good candidate as the biopolymer component of apolymer composite to provide sustained release of silver.

EXAMPLE 4 Determination of Drug Binding to Biopolymer Composite

Polyurethane-gelatin composite sponges of varying gelatin content wereprepared by reacting aqueous solutions of gelatin of varyingconcentration with a standard amount of an anhydrous polyether,polyisocyanate terminated prepolymer (HYPOL® FHP 2002). The resultantsponges were washed, dried, and placed into a dilute solution of silvernitrate. The amount of fluid absorbed into the sponge, the silverconcentration of the sponge, and the silver concentration of thesurrounding solution in equilibrium with the sponge were measured. Fromthe wet weight of the sponge, the passive drug absorption of the spongedue to the fluid content can be calculated. The amount of silver in thesponge in excess of that due to passive fluid absorption is due toactive binding of silver ions:

Bound Drug=[Total Drug in Sample]−[Fluid Content*Solution Concentration]

A method of expressing the drug affinity of a material is by the ratioof “bound drug” to “free drug”:

Bound Drug/Free Drug=Bound Drug/[Total Drug−Bound Drug]

Due to the increased drug affinity for the polymer of the drug reservoira higher Bound/Free ratio provides greater sustained release of drug.FIGS. 9 and 10 describe the results of silver binding to the compositesponges of Example 9. It is readily evident that the gelatin componentgreatly increases the total amount of drug bound to the compositematerial (FIG. 9), thereby creating a drug reservoir. The gelatincomponent also increases the Bound/Free ratio (FIG. 10), providing thedrug affinity for sustained drug release instead of undesired rapid drug“dumping”.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, thescope of the invention is to be limited solely with respect to theappended claims and equivalents.

What is claimed is:
 1. A method for preparing a polymeric deliveryvehicle for controlled-release of a bioactive agent comprising the stepsof treating with a cross-linking agent a biopolymer containingchemically reactive functionalities which react with said cross-linkingagent, wherein said cross-linking agent comprises greater than tworeactive sites per molecule which are chemically reactive with saidfunctionalities, to form a cross-linked biopolymer; optionally, formingsaid cross-linked biopolymer into a desired shape; contacting saidcross-linked biopolymer with a solution containing said bioactive agentto reversibly bind at least a portion of said bioactive agent to saidcross-linked biopolymer to form said polymeric delivery vehicle, whereinthe binding affinity of said cross-linked biopolymer with said bioactiveagent is above 0.8.
 2. A method for preparing a polymeric deliveryvehicle for controlled-release of a bioactive agent comprising the stepsof contacting a biopolymer containing chemically reactivefunctionalities which react with a cross-linking agent with a solutioncontaining a bioactive agent to reversibly bind at least a portion ofsaid bioactive agent to said biopolymer; optionally, forming saidbiopolymer into a desired shape; and treating said biopolymer with across-linking agent wherein said cross-linking agent comprises greaterthan two reactive sites per molecule which are chemically reactive withsaid functionalities, to form said polymeric delivery vehicle, whereinthe binding affinity of said cross-linked biopolymer with said bioactiveagent is above 0.8.
 3. A method according to claim 1 or 2 wherein saidcross-linking agent is selected from the group consisting essentially ofpolyurethanes and polyurethane ureas having isocyanate side groupsand/or end groups.
 4. A method according to claim 1 or 2 wherein themolecular weight of said cross-linking agent is greater than
 500. 5. Amethod according to claim 4 wherein said molecular weight is greaterthan
 1000. 6. A method according to claim 1 or 2 wherein said bindingaffinity is 1.0 or higher.
 7. A method according to claim 6 wherein saidbinding affinity is in the range of 1.0 to 5.0.
 8. A method according toclaim 1 or 2 wherein said step of forming said cross-linked biopolymerinto a desired shape is performed by molding.
 9. A method according toclaim 1 or 2 wherein said biopolymer is selected from the groupconsisting of gelatin, collagen, and polysaccharides.
 10. A methodaccording to claim 1 or 2 wherein said biopolymer comprises chargedgroups and said bioactive agent comprises charged groups whereby thereis binding of said agent and said biopolymer by ionic interaction ofsaid charged groups.
 11. A method according to claim 1 or 2 wherein saidbioactive agent comprises chlorhexidine.
 12. A method according to claim9 wherein said polysaccharide is a cellulose derivative orglycosaminoglycan.
 13. A method according to claim 1 or 2 wherein saidbiopolymer is selected from the group consisting of a protein andpeptide.
 14. A method according to claim 13 wherein said biopolymerfurther comprises silver ions chelated to said protein or peptide.
 15. Amethod according to claim 1 or 2 wherein said bioactive agent comprisesan anti-microbial agent.
 16. A method according to claim 1 or 2 whereinsaid bioactive agent comprises a pharmacological drug.
 17. A methodaccording to claim 1 or 2 wherein said bioactive agent comprises agrowth factor.